ABSATRACT Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the primary cause of dementia in the elderly. There is no cure currently available and the pathogenesis of AD has not been completely elucidated. Considerable evidence supports that A? protein is essential for the pathophysiology and pathogenesis of AD. Notably, A? protein is a physiological protein that is expressed in the brain and can be regulated by neuronal activity and pharmacological modulators and thus has been a premium therapeutic target for AD. This is a multi-institutional and collaborative grant, which is leveraging a state-of-the-art pathopharmacological-physiological program (Drs. Zhang, Gomperts and Tanzi, Mass. General), and cutting- edge biophysical, optical and advanced material technologies (Drs. Ni and Huang, Penn State Univ.), with a goal to modulate, attenuate and detect AD-related pathology. Specifically, the Zhang laboratory has investigated a new class of pharmacological agents, called ?-secretase modulators (GSMs) with AD therapeutic potentials by preferentially decreasing A?42 levels. The Gomperts laboratory has been developed an electrophysiological system to investigate the endophenotypes of hippocampal functions related to AD. a clinical lead GSM molecule appears to normalize dynamic calcium activity of hippocampal neurons in AD transgenic APP/PS1 mice. We recently found that a clinical lead GSM molecule appears to normalize dynamic calcium activity of hippocampal neurons in AD transgenic APP/PS1 mice. Furthermore, the Ni laboratory has developed a high-resolution optogenetic module by utilizing the metasurface-integrated optical fibers which can improve the spatial resolution of light delivery and collection, resulting in light manipulation at designated spot in single neuron levels. The Huang laboratory has developed a two-dimensional (2D) material-based Raman spectroscopy which produces fingerprints of biomolecules allowing enhanced specificity in in-vivo measurements of AD-related proteins. Drs. Ni and Huang also found that integrating 2D materials on an optical fiber can generate enhanced signals with unprecedented uniformity and reproducibility. The goal of this grant is to investigate that the roles of optogenetic (Aim 1) and pharmacological modulation (Aim 2) on AD, with integrated 2D materials-based enhanced Raman spectroscopy and hippocampal functional analysis in live animals. In summary, we envision that our metasurface/2D materials-based optogenetics and Raman spectroscopy will combine with approaches in pharmacology and pathophysiology (MORP), resulting in an integrated platform in freely behaving animals. This platform will focus on both systems level modulating and sensing AD-related proteins and neuronal activity, which should broaden our understanding of AD pathophysiology and facilitate our path for evaluating and developing AD therapeutics.